恶性肿瘤危害人类健康，基于靶标研发高效低毒药物是重要途径之一。课题组曾发现骆驼蓬中7个β-咔啉明显抑制人肺癌细胞生长，后利用6种胞系从β-咔啉骨架2位等多点合成的103个二聚体中筛出10个，优于紫杉醇。但它们脂/水溶性均差，生物利用低而活性受限，且是否经与DNA强作用而具活性仍不清晰。为解决该关键问题，以DNA为靶点，结合β-咔啉单/二聚体的构效关系，采用分子对接筛定两亲性β-咔啉二聚体（N9-N2′/N9′）骨架，据此合成二聚体100个，MTT法测试体外活性，用比较分子力场法（CoMFA、CoMSIA）建立他们与抗肿瘤活性的3D-QSAR模型。对与DNA结合较强候选物，通过细胞周期阻滞测试对DNA复制的影响；利用DNA片段化、荧光谱和自成像、等温滴定量热、原子力显微等5种技术研究他们与胞内、外DNA互作方式和机制，揭示抗肿瘤主要机理，发现新的具有临床前景的两亲性β-咔啉二聚体抗肿瘤药物。

On account of malignant tumors doing harm to people's health, the development of antitumor drugs with high-efficiency and low toxicity based on the target is an important approach. Our group has discovered seven β-carbolines derived from Peganum harmala which significantly inhibited the growth of the human lung cancer cells. Then the biological activity of 10 dimers screened from the 103 bivalent β-carbolines in two and multi-point synthesis through 6 kinds of cells, was better than that of taxol. However, due to their poor fat/water-solubility and low bioavailability, the bioactivity was restricted and whether the bivalent β-carbolines strongly reacted with DNA resulted in unclear activity. To solve the key problem, considering DNA as the target, we will screen the skeleton of amphiphilic bivalent β-carbolines (N9-N2'/N9') using molecular docking to synthesize 100 dimers combining with the structure-activity relationship of β-carboline single/dimer. Then the activity in vitro will be tested by MTT method and 3D-QSAR model between the dimers and their antitumor activity will be built by the comparative molecular force field method (CoMFA, CoMSIA). The candidates strongly combining with DNA will be further studied the effect on DNA replication through the cell cycle arrest test. We will research the mode and mechanism of action between the dimers and intracellular and extracellular DNA utilizing various techniques, such as DNA fragmentation, fluorescence spectrum, self-imaging, isothermal titration calorimetry techniques, atomic force microscope, which will be be capable of revealing antitumor dominant mechanism and in favour of discovering new amphiphilic bivalent β-carbolines anti-tumor drugs with clinical prospects.